Coco-Quinine General Information

An alkaloid derived from the bark of the cinchona tree. It is used as an antimalarial drug, and is the active ingredient in extracts of the cinchona that have been used for that purpose since before 1633. Coco-Quinine is also a mild antipyretic and analgesic and has been used in common cold preparations for that purpose. It was used commonly and as a bitter and flavoring agent, and is still useful for the treatment of babesiosis. Coco-Quinine is also useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, because of its direct effects on muscle membrane and sodium channels. The mechanisms of its antimalarial effects are not well understood. .[PubChem].

Coco-Quinine - Pharmacology:

The theorized mechanism of action for quinine and related anti-malarial drugs is that these drugs are toxic to the malaria parasite. Specifically, the drugs interfere with the parasite's ability to break down and digest hemoglobin. Consequently, the parasite starves and/or builds up toxic levels of partially degraded hemoglobin in itself.

Coco-Quinine for patients

Coco-Quinine Sulfate

324 mg Capsules

This leaflet contains a summary of the most important information about Coco-Quinine Sulfate capsules and should be
read completely before starting your treatment. This leaflet does not replace talking to your doctor or health care
provider about your treatment or medical condition. If you have any questions about your treatment or medical
condition, ask your doctor. Only your doctor or other health care provider can prescribe Coco-Quinine Sulfate and
determine if it is right for you.

Malaria is a serious infection, and if not treated, can be life-threatening. Coco-Quinine Sulfate has been used for
many years as an effective treatment for uncomplicated malaria caused by the parasite Plasmodium
falciparum.

What is Coco-Quinine Sulfate?

Coco-Quinine Sulfate is a prescription medication used in the treatment of uncomplicated malaria caused by the parasite
Plasmodium falciparum. Coco-Quinine Sulfate is NOT approved for the prevention of malaria or for the
prevention or treatment of night-time leg cramps.

What should I tell my doctor or health care provider before taking Coco-Quinine Sulfate?

Tell your doctor or health care provider:

·About all your medical conditions, including any heart, kidney, or
liver problems.

·About all the prescription and non-prescription medications you are
taking, including vitamins and herbal medications.

·If you are pregnant or could be pregnant. Treatment of malaria is
important because it can be a serious disease for a pregnant woman and her unborn baby. Your doctor can tell you
more about the benefits and risks of taking this medication during pregnancy for uncomplicated malaria. You and
your doctor can decide if Coco-Quinine Sulfate is right for you.

·If you are breast-feeding. Small amounts of Coco-Quinine Sulfate can pass
into the breast milk, but no problems with this medicine have been reported in nursing babies. Discuss with your
doctor whether you should breastfeed while taking Coco-Quinine Sulfate.

How should I take Coco-Quinine Sulfate?

·Take Coco-Quinine Sulfate exactly as prescribed.

·Coco-Quinine is a clear capsule that is taken by mouth.

·Unless directed otherwise by your doctor, the usual dose is 648 mg (two 324 mg
capsules) of Coco-Quinine Sulfate every 8 hours by mouth at the same time every day for 7 days.

·To lower the chance of stomach upset, take this medication WITH FOOD.

·Finish all the Coco-Quinine Sulfate that is prescribed even if you feel
better. Do not stop taking the medication without talking to your doctor.

·Do not take more than the amount prescribed. Do not take more than 2 capsules
at one time or more than 3 doses in one day. If you take more than the prescribed dose, call your doctor right
away.

What should I do if I miss a dose?

If you forget to take Coco-Quinine Sulfate, do NOT double the next dose. If it has been more than 4 hours since the
missed dose, WAIT and take the regular dose at the next scheduled time. Call your doctor if you are not sure what to
do.

What are the possible side effects of Coco-Quinine Sulfate?

The most common side effects that you may have when taking Coco-Quinine Sulfate are not usually serious, and will
usually get better when Coco-Quinine Sulfate is stopped. Common side effects with Coco-Quinine Sulfate include:

·Headache ·Nausea

·Sweating ·Flushing

·Ringing in your ears ·Mild hearing loss

·Dizziness · Blurred vision

·Change in color vision

Occasionally, more severe symptoms such as vomiting, diarrhea, and abdominal pain may occur. Rarely, rapid or
irregular heart beat, severe hearing loss, or blindness, may occur. If you experience any severe side effects, call
your doctor.

Elderly patients may be more sensitive to the side effects of quinine than younger patients, and should quickly
report any side effects to their doctor.

Coco-Quinine Sulfate has other less common side effects that are not listed here. For a complete list of side effects,
ask your doctor. If you notice any side effects not mentioned in this leaflet, or if you have any concerns about a
side effect you are having, talk to your doctor.

Coco-Quinine Sulfate is NOT approved for the treatment of leg cramps because quinine has not been proven to work
for this condition, and may cause serious or life-threatening side effects. Some of the more serious side effects of
quinine are blindness, deafness, and abnormal heart rhythm. Your doctor can tell you additional information about
serious side effects reported with Coco-Quinine Sulfate.

Call your doctor or health care provider right away if:

·You feel worse; or if you do not start feeling better within a day or two of
taking Coco-Quinine Sulfate.

·If your fevers come back after completing treatment with Coco-Quinine Sulfate, call
your doctor to make sure that the malaria has not returned.

o Other problems: abnormal bleeding (such as severe nosebleed, and blood in the urine, or stool),
severe bruising, or the appearance of unusual purple-brown or red spots on your skin.

What about other medications I am taking?

·Tell your doctor about all other prescription and non-prescription
medications

you are taking, including vitamins and herbal supplements.

·Certain medications should be avoided when you are taking Coco-Quinine Sulfate.

·Your doctor has a list of medications that should be avoided or which may
require special precautions while taking Coco-Quinine Sulfate.

How do I store Coco-Quinine Sulfate?

Keep Coco-Quinine Sulfate out of reach of children. Keep the capsules in a tightly closed container. Do not
refrigerate or freeze. Store at room temperature; 25-30°C (77-86°F).

General advice about Coco-Quinine Sulfate:

Do not use Coco-Quinine Sulfate for a condition for which it was not prescribed. Do NOT give Coco-Quinine Sulfate to other
people, even if they have the same symptoms, because it may be harmful.

This leaflet highlights the most important information about Coco-Quinine Sulfate. For more information, you should
talk with your doctor or health care provider.

Active Ingredients: Coco-Quinine Sulfate, USP

Inactive Ingredients: Corn starch, magnesium stearate, talc

Coco-Quinine Interactions

Effects of Drugs and Other Agents on Coco-Quinine Pharmacokinetics

Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine.
Concomitant administration of these antacids with quinine should be avoided.

Cholestyramine: In 8 healthy volunteers who received quinine sulfate 600 mg with or without 8 grams of
cholestyramine resin, no significant difference in quinine pharmacokinetic parameters was seen.

Erythromycin (CYP3A4 inhibitor): Erythromycin was shown to inhibit the metabolism of quinine in
vitro using human liver microsomes. Therefore, concomitant administration of erythromycin with quinine sulfate is
likely to increase plasma quinine concentrations, and should be avoided.

Grapefruit juice (CYP3A4 inhibitor): In a pharmacokinetic study involving 10 healthy volunteers, the
administration of a single 600 mg dose of quinine sulfate with grapefruit juice (full-strength or half-strength) did
not significantly alter the pharmacokinetic parameters of quinine. Coco-Quinine sulfate may be taken with grapefruit
juice.

Histamine H2-receptor blockers (cimetidine, ranitidine): In healthy volunteers who were given a single oral
600 mg dose of quinine sulfate after pretreatment with cimetidine (200 mg three times daily and 400 mg at bedtime for
7 days) or ranitidine (150 mg twice daily for 7 days), the apparent oral clearance of quinine decreased and the mean
elimination half- life increased significantly when given with cimetidine but not with ranitidine. Compared to
untreated controls, the mean AUC of quinine increased by only 20% with ranitidine and by 42% with cimetidine
(p<0.05) without a significant change in mean quinine Cmax. When quinine is to be given concomitantly
with a histamine H2 receptor blocker, the use of ranitidine is preferred over cimetidine. Although
cimetidine may be used concomitantly with quinine sulfate, patients should be monitored closely for adverse events
associated with quinine.

Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic
parameters of quinine. Adjustment of quinine dosage is not necessary when isoniazid is given concomitantly.

Ketoconazole (CYP3A4 inhibitor): In a crossover study, healthy subjects (N=9) who received a single oral
dose of quinine hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean
quinine AUC that was higher by 45% and a mean oral clearance of quinine that was 31% lower than after receiving
quinine alone. Although no change in the quinine dosage regimen is necessary with concomitant ketoconazole, patients
should be monitored closely for adverse reactio ns associated with quinine sulfate.

Oral contraceptives (estrogen, progestin): In 7 healthy females who were using single ingredient progestin
or combination estrogen-containing oral contraceptives, the pharmacokinetic parameters of a single 600 mg dose of
quinine sulfate were not altered in comparison to those observed in 7 age- matched female control subjects not using
oral contraceptives.

Rifampin (CYP3A4 inducer): In patients with uncomplicated P. falciparum malaria who received quinine
sulfate 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of quinine between days 3
and 7 of therapy was 75% lower as compared to those who received quinine monotherapy. In healthy volunteers (N=9) who
received a single oral 600 mg dose of quinine sulfate after 2 weeks of pretreatment with rifampin 600 mg/day, the
mean quinine AUC and C max decreased by 85% and 55%, respectively. Therefore the concomitant administration of
rifampin with quinine sulfate should be avoided .

Tetracycline: In 8 patients with acute uncomplicated P. falciparum malaria who were treated with
oral quinine sulfate (600 mg every 8 hours for 7 days) in combination with oral tetracycline (250 mg every 6 hours
for 7 days), the mean plasma quinine concentrations were about two- fold higher than in 8 patients who received
quinine monotherapy. Although tetracycline may be concomitantly administered with quinine sulfate, patients should be
monitored closely for adverse reactions associated with quinine sulfate.

Troleandomycin (CYP3A4 inhibitor): In a crossover study (N=10), healthy subjects who received a single oral
600 mg dose of quinine sulfate with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87%
higher mean quinine AUC, a 45% lower mean oral clearance of quinine, and a 81% lower formation clearance of the main
metabolite, 3-hydroxyquinine, than when quinine was given alone. Therefore, concomitant administration of
troleandomycin with quinine sulfate should be avoided.

Results of in vivo and in vitro drug interaction studies suggest that quinine has the potential to
inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6, as well as inhibit the biliary excretion of
drugs like digoxin.

Anticonvulsants (carbamazepine, phenobarbital, and phenytoin): A single 600 mg oral dose of quinine sulfate
increased the mean plasma C max, and AUC0-24 of single oral doses of carbamazepine (200 mg) and
phenobarbital (120 mg) but not phenytoin (200 mg) in 8 healthy subjects. The mean AUC increases of carbamazepine,
phenobarbital and phenytoin were 104%, 81% and 4%, respectively; the mean increases in C max were 56%, 53%, and 4%,
respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by
quinine. If concomitant administration with carbamazepine or phenobarbital cannot be avoided, frequent monitoring of
anticonvulsant drug concentrations is recommended. Additionally, patients should be monitored closely for adverse
reactions associated with these anticonvulsants. Carbamazepine, phe nobarbital, and phenytoin are CYP3A4 inducers and
may decrease quinine plasma concentrations if used concurrently with quinine sulfate.

Astemizole (CYP3A4 substrate): Elevated plasma astemizole concentrations were reported in a subject who
experienced torsades de pointes after receiving three doses of quinine sulfate for nocturnal leg cramps concomitantly
with chronic astemizole 10 mg/day. The concurrent use of quinine with astemizole and other CYP3A4 substrates with QT
prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide, and quinidine ) should also be
avoided

Desipramine (CYP2D6 substrate): Coco-Quinine (750 mg/day for 2 days) decreased the metabolism of desipramine in
patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers.
Lower doses (80 mg to 400 mg) of quinine did not significantly affect the pharmacokinetics of other CYP2D6
substrates, namely, debrisoquine, dextromethorphan, and methoxyphenamine. Although clinical drug interaction studies
have not been performed, antimalarial doses (greater than or equal to 600 mg) of quinine may inhibit the metabolism
of other drugs that are CYP2D6 substrates (e.g., flecainide, debrisoquine, dextromethorphan, metoprolol,
paroxetine ). Patients taking medications that are CYP2D6 substrates with quinine sulfate should be monitored
closely for adverse reactions a sociated with these medications.

Digoxin: In 4 healthy subjects who received digoxin (0.5 to 0.75 mg/day) during treatment with quinine (750
mg/day), a 33% increase in mean steady state AUC of digoxin and a 35% reduction in the steady-state biliary clearance
of digoxin were observed compared to digoxin alone. Thus, if quinine is administered to patients receiving digo xin,
plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary.

Halofantrine: Although not studied clinically, quinine was shown to inhibit the metabolism of halofantrine
in vitro using human liver microsomes. Therefore, concomitant administration of quinine sulfate is likely to
increase plasma halofantrine concentrations.

Mefloquine: In 7 healthy subjects who received mefloquine (750 mg) at 24 hours before an oral 600 mg dose
of quinine sulfate, the AUC of mefloquine was increased by 22% compared to mefloquine alone. In this study, the QTc
interval was significantly prolonged in the subjects who received mefloquine and quinine sulfate 24 hours apart. The
concomitant administration of mefloquine and quinine may produce electrocardiographic abnormalities (including QTc
prolongation) and may increase the risk of seizures.

Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, quinine
potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and
subsequently (3 hours after receiving pancuronium) received quinine 1800 mg daily. Coco-Quinine may also enhance the
neuromuscular blocking effects of succinylcholine and tubocurarine .

Warfarin and oral anticoagulants: Cinchona alkaloids, including quinine, may have the potential to depress
hepatic enzyme synthesis of vitamin K-dependent coagulation pathway proteins and may enhance the action of warfarin
and other oral anticoagulants. Coco-Quinine may also interfere with the anticoagulant effect of heparin. Thus, in patients
receiving these anticoagulants, the prothrombin time (PT), partial thromboplastin time (PTT), or international
normalization ratio (INR) should be closely monitored as appropriate, during concurrent therapy with quinine.

Drug/Laboratory Interactions: Coco-Quinine may produce an elevated value for urinary 17-ketogenic steroids when
the Zimmerman method is used.

Coco-Quinine Contraindications

Coco-Quinine is contraindicated in patients with known hypersensitivity, in pregnancy, in women of child bearing potential, in patients with glucose-6-phosphate dehydrogenase deficiency, in patients with tinnitus, or optic neuritis, and in patients with a history of blackwater fever.